PROJECT SUMMARY Alcohol use disorder is one of the leading causes of morbidity and mortality worldwide. Unfortunately, effective therapies for alcohol-related diseases are still lacking. Increasing evidence suggest that alteration of intestinal microbiota (dysbiosis) contributes to alcohol-induced intestinal and liver injury. The mechanism of how alcohol hampers host defense response against dysbiosis remains largely unclear. Our preliminary data showed that alcohol exposure 1) causes enteric dysbiosis and intestine/liver injury; 2) dramatically decreases intestinal dual oxidase 2 (DUOX2), an NADPH oxidase that is involved in oxidative innate immune defense to bacterial dysbiosis; 3) diminishes intestinal IL-22, which is a potent regulator of DUOX2 expression; and 4) reduces the bioavailability of intestinal tryptophan catabolites, that are implicated in orchestrating IL-22, in mice. The goal of the project is to delineate a fundamental role of DUOX2 in maintaining host-microbe symbiosis against alcohol intoxication. It is also set to explore a pathological link between the impaired tryptophan-IL-22 pathway and DUOX2 dysfunction. The hypothesis will be tested in 3 Aims. Studies in Aim 1 will investigate the effect of DUOX2 dysfunction on alcohol-perturbed host-microbiota symbiosis; Aim 2 will determine if IL-22 reduction is a causal factor of alcohol-diminished DUOX2; Aim 3 will test if tryptophan catabolite is capable of restoring alcohol-reduced IL-22-DUOX2 signaling. Overall, the project will yield novel insights into the mechanism by which DUOX2 dysfunction contributes to host-microbiota dyshomeostasis upon alcohol intoxication and may help in developing better therapeutic strategies for alcohol-related diseases.